Antibody-based approaches in Alzheimer's research: safety, pharmacokinetics, metabolism, and analytical tools

High morbidity, enormous socioeconomic costs, and lack of specific treatments emphasize the importance of research on protective therapies against Alzheimer's disease. The efficacy of anti-amyloid immunization strategies has been demonstrated preclinically, prompting the design of clinical studies. However, the detailed mechanisms of action of therapeutic antibodies, especially their influence on the complex amyloid a peptide (A beta) metabolism and various A beta-equilibria present both within and outside the CNS, are far from being clear. Furthermore, physiological A beta metabolism is poorly understood and the analytical tools to characterize and quantify treatment effects on A beta metabolism are suboptimal. Thus, the design of immunization strategies with optimized benefit-to-risk ratios for patients is subjected to significant obstacles. Indeed, an active immunization trial with A beta was discontinued because of severe adverse effects. Anti-A beta immunization protocols designed to attain high blood. levels of antibodies bear the potential to induce brain inflammation and/or hemorrhage, thus directing the biomedical research towards development of more predictable therapies for minimizing the risk of adverse effects. The focus of this review is to summarize current knowledge of A beta metabolism under physiological and antibody-based therapeutic conditions and to introduce a promising approach, namely the passive immunization using antibody fragments, which are characterized by entirely different pharmacokinetic and pharmacodynamic properties compared with conventional monoclonal antibodies.